Method and device for accurate dispensing of radioactivity

ABSTRACT

A method of delivering a radioactive liquid includes, performing an initialization, including; extracting at least a first amount of a radioactive liquid from a source of radioactive liquid, measuring a radioactivity level for the first amount of radioactive liquid, and performing a calibration phase. The calibration phase includes, extracting a second amount of radioactive liquid from the source of radioactive liquid wherein the second amount is calculated based on the radioactivity level of the first amount to provide a total dose of radioactive liquid having a predetermined radioactivity level, and delivering the total dose and performing at least one more calibration and delivery phases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 14/505,861, filed Oct. 3, 2014, now granted U.S.Pat. No. 9,295,857, which is a continuation of U.S. patent applicationSer. No. 13/965,670, filed Aug. 13, 2013, now granted U.S. Pat. No.8,852,071, which is a divisional application of U.S. patent applicationSer. No. 11/572,123, filed Oct. 15, 2008, now granted U.S. Pat. No.8,517,905, which claims priority to PCT Application No.PCT/CH2005/000403 filed Jul. 14, 2005, expired, which claims priority toEP application No. 04405459, filed Jul. 16, 2004.

BACKGROUND OF THE INVENTION

The present invention relates to a device and a method for dispensing, aradioactive liquid to a destination. In particular, the inventionrelates to the problem of accurately dispensing a well-determined doseof radioactivity, e.g., for injection to a living body.

In a number of medical applications, it is necessary to, deliver aradiopharmaceutical containing a radionuclide to a patient. Due to theionizing radiation emitted by the radionuclide, such pharmaceuticalspose a danger to both the patient and the personnel administering theradiopharmaceutical if not handled properly.

Examples for diagnostic uses of radiopharmaceuticals include positronemission tomography (PET) and single-photon emission computerizedtomography (SPECT). In these methods, a patient is injected a dose of aradiopharmaceutical which can be absorbed by certain cells in the brainor in other organs. The concentration of the accumulatedradiopharmaceutical in a specific body part will often depend on factorsof diagnostic interest, such as cell metabolism or other physiologicalor biochemical processes. Thus, such processes can be imaged in anon-invasive fashion by determining the spatio-temporal distribution ofradioactivity within the body part of interest. In PET, this is achievedby monitoring pairs of temporally coincident gamma rays emitted inopposite directions resulting from the annihilation of positrons, whichare emitted through beta-plus decays of the (proton-rich) radionuclide.The most common radionuclides radioisotopes) for use with PET are ¹⁵O,¹⁸F, ¹¹C, ¹³N and ⁸²Rb. Radiopharmaceuticals of interest for PETinclude, but are not limited to, substances like [¹⁵O]—H₂O,[¹⁸F]-fluorodeoxyglucose ([¹⁸F]-FDG), [¹⁸F]-fluoromisonidazole([¹⁸F]-FMISO), [¹¹C]-labeled amino acids, [¹³N]-ammonia etc.

The most common therapeutic uses of radiopharmaceuticals are the ¹³¹Itherapies in thyroid diseases.

In these applications, it is desirable to administer an exactlydetermined dose of radiopharmaceutical to the body. Often theradiopharmaceutical is delivered in a vial from which it has to bedispensed into individual patient doses. In many centers this is amanual process done by the technical personnel. Since the concentrationof the radiopharmaceutical in the vial can be very high, the manualdispensing is associated with considerable radiation burden to thehands. Furthermore the accuracy of the manual dispensing is limited anddependent on the experience of the person in charge.

As an example, U.S. Pat. No. 4,410,108 discloses a syringe shieldequipped with a radiation detector. A liquid radiopharmaceutical isdrawn from a vial into the barrel of a syringe placed within the syringeshield, while the level of radioactivity within the barrel is monitoredby the radiation detector. In this way, an aliquot of theradiopharmaceutical having exactly the required dose of radioactivitycan be drawn into the syringe. Subsequently, the syringe with its shieldis manually removed from the vial, and the radiopharmaceutical isinjected to the patient. This device is unsatisfactory in requiringmanual transfer of the syringe after it has been filled with theradiopharmaceutical, as this may expose the personnel handling thesyringe to ionizing radiation. Although the half-life of theradiopharmaceutical is usually rather short and the applied dosages arethemselves not harmful, constant and repeated exposure over an extendedperiod of time can be harmful.

A number of techniques have been proposed to reduce exposure byminimizing the time of exposure of personnel, by maintaining distancebetween personnel and the source of radiation, and by shieldingpersonnel from the source of radiation. As an example, European patentapplication EP 0 486 283 discloses a system for delivering H₂ ¹⁵O. Acollection bottle is filled with saline, then a fluid stream comprisingH₂ ¹⁵O is passed through the collection bottle while the activity inthis bottle is monitored by a radiation detector. When a desired levelof radiation is reached, the liquid in the bottle is transferred to amotor-driven syringe and then injected to the patient body. U.S. patentapplication publication No. 2003/0004463 also discloses a system fordispensing a radiopharmaceutical in a remote fashion, without the needof manual intervention. The radiopharmaceutical is drawn from a vialinto a syringe surrounded by a radiation detector, and the level ofradioactivity in the syringe is determined. Through specially adaptedtubing and valves, the radiopharmaceutical is subsequently delivered toa patient without the need of moving the syringe to another location.

While these systems obviate the need of manual handling of a syringe,they tend to be imprecise in situations where small amounts ofradioactive liquid, possibly with a very high concentration of activity,need to be handled, due to the presence of dead volumes. By the way ofexample, the radiopharmaceutical may come in a vial at an activityconcentration of 2 GBq/ml (one billion Becquerels per milliliter). Ifthe required activity for injection to the patient is, say, 100 MBq, avolume of just 50 microliters needs to be transferred from the vial tothe patient. Such small amounts of liquid are difficult to handle withthe systems of the prior art.

U.S. Pat. Nos. 4,562,829 and 4,585,009 disclose strontium-rubidiuminfusion systems equipped with an in-line radiation detector. Aradiopharmaceutical exiting a strontium-rubidium generator flows pastthe radiation detector, which monitors the activity of theradiopharmaceutical in passing. From there, the radiopharmaceutical iseither administered to a patient or is sent to waste. In U.S. Pat. No.4,409,966, a flow of patient blood is shunted through a radiationdetector during injection of the radiopharmaceutical, and the level ofradioactivity in the blood is monitored. Also with such systems, it isdifficult to administer an exactly determined dose, especially forconcentrated radiopharmaceuticals with high specific activities, as thevolume of the tubing already may exceed the desired volume to beinjected.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to provide a device which iscapable of accurately dispensing a desired level of radioactivity in aliquid, and which may be operated remotely.

Thus, according to the invention, a source of a radioactive liquid and asource of a flushing liquid can be selectively connected to a fluiddelivery path by way of valve means. An activity metering unit isoperable to determine a level of radioactivity in a metering section ofthe fluid delivery path downstream from the valve means. In this way, itis possible to provide some amount, even a very small amount, of theradioactive liquid to a section of the fluid delivery path adjacent tothe valve means. The flushing liquid can then be used to flush thisamount of radioactive liquid to the metering section, where its activitycan be determined and further steps to be taken can be decided based onthis determination of activity. By use of valve means adapted for remotecontrol (e.g. an electromagnetically or pneumatically operated valve),operation of the inventive device can be performed remotely.

It is a further object of the present invention to provide a method ofoperation of such a device.

Thus, according to the invention, the device is operated by transportinga first amount of radioactive liquid to the metering section, using theactivity metering unit to measure a reference level of radioactivity,calculating a second amount of the radioactive liquid still to bedelivered such that the first and second amounts of radioactive liquidtogether have some predetermined level of radioactivity, and deliveringthe first and second amounts of radioactive liquid to the destination.In this way, it is possible to deliver an exactly known level ofradioactivity to the destination, independent of the activityconcentration of the radioactive liquid. Preferably, the first amount ofradioactive liquid is between 20% and 80% of the sum of the first andsecond amounts of radioactive liquid, more preferably between 30% and70%, most preferably between 40% and 60%. In this way, high precisioncan be achieved.

In an advantageous embodiment of the inventive device, the deviceadditionally comprises a control unit. The unit receives signals fromthe activity metering unit and controls operation of the valve meansbetween at least two states. In the first state, the source ofradioactive liquid is connected to the fluid delivery path for flow ofthe radioactive liquid into the fluid delivery path. In the secondstate, the source of flushing liquid is connected to the fluid deliverypath for flow of flushing liquid into the fluid delivery path. If anyother actively driven components are present in the device, such asadditional valves or pumps, they may also be controlled by the controlunit.

Advantageously, second valve means are provided downstream from themetering section for directing flow in the fluid delivery path either tothe destination or to a waste reservoir. In this way it is avoided thatthe destination receives excessive amounts of flushing liquid duringoperation of the device, and in case of malfunctioning of components ofthe device, the radioactive liquid can be dumped to the waste reservoir.

Advantageously, a first and/or a second pump are provided for pumpingthe radioactive liquid or the flushing liquid, respectively, through thefirst valve means and into the fluid delivery path. Preferably, thefirst pump and/or the second pump is operable to receive a controlsignal and to deliver a predetermined volume of liquid based on thecontrol signal. In this way, exactly known amounts (volumes) of theradioactive liquid and/or of the flushing liquid can be dispensed to thefluid delivery path.

The fluid delivery path may comprise a fill-in section extending fromthe first valve means to the metering section. Advantageously, themetering section is capable of holding a fluid volume which is at leastthree times, more preferably at least five times the volume of thefill-in section. This enables the metering section to hold at least two,preferably three, fractions of radioactive liquid, each with a volume upto the volume of the fill-in section, plus the flushing liquid requiredto flush these fractions into the metering section. Thereby, the totalactivity of two, preferably three, fractions of radioactive liquid maybe determined in a single measurement by the activity metering unit.

Advantageously, the device is adapted for delivering aradiopharmaceutical for injection to a living body for delivering theradiopharmaceutical to an injection needle). This encompasses, amongother things, the use of compatible materials, which most be resistantto the radiopharmaceutical and the flushing liquid (usually salinesolution in this case), and which must be able to withstandsterilization procedures. Such materials are well known.

As used herein, the term “pharmaceutical” refers to any substance to beinjected or otherwise delivered into the body (either human or animal)in a medical procedure and includes, but is not limited to, substancesused in imaging procedures and therapeutic substances. The term“radiopharmaceutical” refers to any pharmaceutical emitting ionisingradiation by radioactive decay.

Further advantageous embodiments of the invention are laid down in thedependent claims. In particular, the inventive method may comprise anadditional initialization procedure, in which an offset amount ofradioactive liquid is transported to the metering section, an offsetlevel of radioactivity is determined, and the predetermined level ofradioactivity for the main procedure is determined from this offsetlevel and a desired level of radioactivity to be dispensed.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in more detail in connection with anexemplary embodiment illustrated in the drawings, in which

FIG. 1 shows a schematic and simplified illustration of a deviceaccording to the present invention;

FIG. 2 shows a schematic and simplified illustration of a dosecalibrator;

FIGS. 3A and 3B show simplified illustrations of a pinch valve;

FIG. 4 illustrates a first state of operation of the device of FIG. 1;

FIG. 5 illustrates a second state of operation of the device of FIG. 1;

FIG. 6 illustrates a third state of operation of the device of FIG. 1;

FIG. 7 illustrates a fourth state of operation of the device of FIG. 1;

FIG. 8 illustrates a fifth state of operation of the device of FIG. 1;

FIG. 9 shows a flow diagram of a process according to the presentinvention; and

FIG. 10 illustrates the levels of activities measured in various stagesof the process of FIG. 9.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 shows, in a highly schematic manner, a device for dispensing aradioactive liquid according to a preferred embodiment of the presentinvention. The device is designed for dispensing a radiopharmaceuticalfor injection to a patient.

The radiopharmaceutical 1 is provided in a vial 2. In order to protectthe surroundings from radioactivity originating from the vial 2, thevial 2 is placed inside a shield 3. Suitable vials and shields forvarious kinds of radiopharmaceuticals are well known in the art and areavailable commercially.

A section 4 of tubing, comprising a needle at its end for puncturing aseptum closing off vial 2, extends from the inside of vial 2 through afirst peristaltic precision pump P1 and to a first three-way pinch valveV1. At its first port “a”, the valve V1 is connected to the section 4 oftubing from the vial 2; at its second port “b”, it is connected to asection of tubing 7 extending from the valve V1 to an activity meteringunit 9 (in the following shortly called a “dose calibrator”). The thirdport “c” is connected to a section 6 of tubing leading from a salinereservoir 5 through a second peristaltic precision pump P2 to the valveV1. The valve V1 is operable to connect port “a” with port “b” or toconnect port “c” with port “b”.

FIGS. 3A and 3B illustrate, in a highly schematic manner, the mode ofoperation of the pinch valve V1 as advantageously used in the presentembodiment. A sliding element 31 can be moved up or down, pressingeither on an upper or on a lower section of flexible tubing which ispassed through the pinch valve. Thereby, either port “c” or port “a” isclosed off from port “b”, and the other port is connected to port “b”.The sliding element 31 may, e.g., be operated electromechanically orpneumatically. A similar pinch valve is used as valve V2. Such pinchvalves are advantageous because no moving parts get into contact withthe liquid within the tubing. Thus the valve cannot get contaminated byradioactive liquid possibly present in the tubing.

The pumps P1 and P2 are preferably peristaltic precision pumps. In aperistaltic pump, a section of flexible tubing is passed through thepump unit. Fluid is forced along the tubing by waves of contractionproduced mechanically on the flexible tubing. Peristaltic pumps offerthe advantage that the liquid is always contained in the tubing, and nomoving parts get into contact with the liquid to be delivered. Thus thepump itself cannot be contaminated by radioactive liquid present in thetubing. By the use of peristaltic pumps and pinch valves, theconnections from the saline reservoir 5 to the metering section 7 andfrom the vial 2 to the metering section 7 may consist of a single pieceof flexible tubing each, which can be easily replaced in regularintervals to avoid cross-contamination, without the need to replace themuch more expensive pump and valve assemblies themselves.

The section 7 of tubing may be called a “fill-in section”. This fill-insection 7 is connected to a section 8 of tubing placed inside the dosecalibrator 9, section 8 being called a “metering section”. The meteringsection 8 is relatively long, providing a volume of at least five timesthe volume of the fill-in section, by having a meander-like shape orpreferably, a coil shape as illustrated for a metering section 8′ inFIG. 2. A coil shape is preferred in practice because it minimizespressure losses during fluid flow. The meander-like shape has beenchosen in FIGS. 1 and 3-7 for illustrative purposes.

The tubing exits the dose calibrator 9 and connects to the first port“d” of a second three-way valve V2. The second port “e” of this valve isconnected to a section 10 of tubing leading to an injection needle 11,only crudely symbolized by a triangle in FIG. 1. The third port “f” ofvalve V2 leads to a waste reservoir 12. The waste reservoir 12 ispreferably shielded, as radioactivity may enter in operation.

The dose calibrator 9 is connected to a controller 13 and providessignals to the controller 13 which are indicative of the level ofactivity within the dose calibrator 9. The outputs of the controller 13are connected to the pumps P1 and P2 as well as to the valves V1 and V2for control of these.

A method of operation of the device is illustrated in FIGS. 4 to 8 andsymbolized in a flow diagram in FIG. 9. Operation can generally bedivided into five phases: in an initialisation phase 910, the device isbrought into a well-defined initial state. In a calibration phase 920,steps are performed for calibrating the radioactivity in vial 2. In adelivery phase 930, the radiopharmaceutical is delivered to thedestination. In a step 940, it is decided whether another injectionshall be performed. If yes, operation will continue again with thecalibration phase 920; if not, a shutdown phase 950 will follow.

Before starting the operation, the operator will have to determine twoquantities: the desired activity Ar to be injected to the patient, andthe estimated concentration of activity in the vial (activity per unitof volume, expressed in MBq/ml), Cv. These data are provided to thecontroller 13. Operation then starts with the initialisation period 910.

The initialisation period 910 comprises the following steps:

Step 911 (Initial filling of radiopharmaceutical to point C): In a firststep, the complete tubing is filled with saline, thereby excluding airfrom the tubing system. For this, valve V1 is switched into a stateconnecting ports “c” and “b”, while valve V2 connects “d” and “e”. PumpP2 flushes saline up to point B (cf. FIG. 4). Then the tubing section 4is inserted into a vial containing saline Valve V1 is brought into astate connecting ports “a” and “b”, while valve V2 still connects “d”and “e”. Pump P1 now flushes saline until the tubing is completelyfilled with saline from point A (cf. FIG. 4) to the destination beyondvalve V2, and air is thus completely purged from the system. The tubingsection 4 is then inserted into the vial 2 containing theradiopharmaceutical. Valve V1 is brought into a state connecting ports“a” and “b”, while valve V2 connects ports “d” and “f”. Pump P1 isoperated to pump radiopharmaceutical 1 from inlet point A and past pointB at valve V1 to some point C in the fill-in section 7. The volume ofradiopharmaceutical between points B and C in the fill-in section 7 doesnot need to be known exactly; it suffices to ensure that the section oftubing from A to B is filled completely with radiopharmaceutical, andthat the activity in the volume between B and C is not larger than thedesired end activity Ar. The situation at the end of step 911 isillustrated in FIG. 4, where the volume of radiopharmaceutical betweenpoints B and C is designated by reference number 21.

Step 912 (Flushing of offset volume to dose calibrator): Valve V1 is nowswitched to a state in which it connects ports “c” and “b”. Pump P2 isoperated to pump saline from the saline reservoir 5 towards valve V1.The volume to be pumped is slightly larger than the volume in thefill-in section 7 of the tubing, i.e. slightly larger than the volumebetween points B and D. This volume need not be known exactly. Thereby,the “offset volume” 21 is moved into the metering section 8. Thesituation at the end of this step is illustrated in FIG. 5.

Step 913 (Initial determination of activity): The activity of volume 21in the metering section 8 is measured by the dose calibrator 9(measurement M1). This activity will be called the “offset activity” A1.The controller 13 now calculates the missing activity Am required toreach a total activity of Ar: Am=Ar−A1. This is illustrated in FIG. 10in the leftmost column. From this and the estimated concentration ofactivity in the vial, Cv, the estimated missing volume Va1 still to bedelivered is calculated: Va1=Am/Cv. It is important to note that thiscalculation is still based on the estimate of the concentration ofactivity in the vial, and the result cannot be expected to be highlyaccurate. It is further important to note that no knowledge about theoffset volume 21 is required in this calculation.

This step concludes initialisation 910. In the following calibrationphase 920, the following steps are performed:

Step 921 (Filling of radiopharmaceutical to point C′): Valve V1 isswitched to a state in which it connects ports “a” and “b”. Pump P1 isoperated to pump a volume Vc′ through valve V1, filling the fill-insection to point C′. This situation is illustrated in FIG. 6, where thisvolume is designated by reference number 22. Volume Vc′ is chosen to beapproximately half of the estimated missing volume Va1: Vc′=Va1/2. It isimportant to note that volume Vc′ is known exactly in system internalunits. The exact nature of these units depends on the type of pump used,e.g., the units could be pump revolutions, pump cycles etc. If a volumeflow meter is placed in-line with the pump, the units provided by theflow meter can be used as system internal units. Depending on the typeof pump and the type of tubing, the resolution of volume in this stepcan be very small, and even small volumes can be delivered accurately.

Step 922 (Flushing of volume Vc′ to dose calibrator): Valve V1 isswitched to connect ports “c” and “b”. Pump P2 is operated to pumpslightly more than the volume between points B and D of saline throughvalve V1. Thereby, volume 22 (=Vc′) of radiopharmaceutical is moved intothe metering section 8. The situation at the end of this step isillustrated in FIG. 7.

Step 923 (Calibration of activity): The activity in the metering section8 is measured by the dose calibrator 9 (measurement M2). This activitylevel will be called A2. It corresponds to the sum of the offsetactivity A1 and the activity of the volume Vc′, which will be called the“reference activity” Ac′. This is illustrated in the second column ofFIG. 10. Now the activity concentration in the vial in system internalunits, Cs, is calculated: Cs=Ac′/Vc′=(A2=A1)/Vc′. The system is nowcalibrated in system internal units.

Step 924 (Determination of volume Vc″): The activity Ac″ still requiredto reach a total activity of Ar is determined: Ac″Ar−A2. From this, thevolume Vc″ still to be delivered is calculated in system internal units:Vc″=Ac″/Cs=(Ar−A2)/Cs=(Ar−A2)/(A2−A1)*Vc′.

This completes the calibration phase 920. In the following deliveryphase 930, the following steps are performed:

Step 931 (Filling of radiopharmaceutical to point C″): Valve V1 isswitched to a state in which it connects ports “a” and “b”. Pump P1 isoperated to pump the volume Vc″ through valve V1, filling the fill-insection to point C″. This situation is illustrated in FIG. 8, where thisvolume is designated by reference number 23.

Step 932 (Flushing of volume Vc″ to dose calibrator): Valve V1 isswitched to connect ports “c” and “b”. Pump P2 is operated to pumpslightly more than the volume between points B and D of saline throughvalve V1. Thereby, volume 23 (=Vc″) of radiopharmaceutical is moved intothe metering section 8. Optionally, the total activity in the meteringsection is now measured (optional measurement M3, see right column ofFIG. 10). It should correspond exactly to the total desired activity Ar,provided that the volume of the metering section is large enough to holdall three volumes 21, 22 and 23 within this section. The lattercondition is can always be fulfilled if the volume of the meteringsection 8 is at least five times the volume of the fill-in section 7. Ifa significant discrepancy is detected, the system is stopped.

Step 933 (Delivery to injection needle): Valve V2 is switched to connectports “d” and “e”. Pump P2 is operated to pump at least the volume ofthe metering section 8, plus the volume of the tubing from the meteringsection to the injection needle and of the injection needle itself, ofsaline through valve V1. Thereby, all liquid in the metering section 8is flushed to the patient, and exactly the required dose ofradioactivity is delivered to the patient.

This completes the delivery phase 930. If another injection of the sameradiopharmaceutical (to the same or a different patient) is required,operation continues by repeating the calibration and delivery phases 920and 930. Otherwise, operation stops by a suitable shutdown procedure,which may involve additional cycles of flushing with saline.

When repeating calibration phase 930, no additional initialisation as inphase 910 is necessary, since the metering section 8 has been flushedwith saline, and the radiopharmaceutical extends exactly to point B. Noactivity is present in the metering section 8. Therefore, in the abovecalculations, A1 can be set to zero in this case, and Am is set to Ar.No further changes are necessary. The three-phase procedure with phases910, 920 and 930 now simplifies to a two-phase procedure with phases 920and 930 only.

It will be appreciated that the device of the present invention and theassociated method of operation provide a number of inherent safetyfeatures. Specifically, there is a high degree of redundancy in theoperation of the device, such that even in case of failure of onecomponent, such as a pump or a valve, it is impossible that more thanthe desired dose will be delivered to the patient. Specifically, by itsdesign the system will only allow the dose present within the meteringsection 8 to be delivered to the patient. This is because during theactual delivery of the radiopharmaceutical there is no connectionbetween the vial 2 and the fluid delivery line. The discrete nature ofthe sequential measurements of activity within the metering section 8 isanother feature which increases safety: In step 932, the activity in themetering section 8 is actually known beforehand, and measurement M3 justserves to confirm that the right amount of activity is present in themetering section 8. If significant discrepancies are detected betweenthe expected result and the actual measurement, operation will bestopped immediately, and an alarm will be given.

It will also be appreciated that, in normal operation, noradiopharmaceutical will enter the waste reservoir 12. Thus, generationof radioactive waste is minimized.

A device according to the present invention in the embodiment of FIG. 1has been set up and tested in practice. The device was assembled fromstandard components available commercially. For the tubing sections 4and 6, flexible tubing made from silicone with an inner diameter of 1.52mm was used. The pumps P1 and P2 were peristaltic precision pumps (P1:Ismatec™ ISM 596B, P2: Arcomed™ Volumed™ mVp 5000). The valves V1 and V2were electrically operated pinch valves available from Bio-Chem ValveInc. The metering section 8′ of tubing had a coil shape with ninewindings and a diameter of 3.5 cm, made from fluoro-ethylene-propylene.A Veenstra VDC 405 dose calibrator was used as activity meteringunit/dose calibrator 9. The complete assembly was shielded by a 5 cmlead shield. As a controller 13, a standard personal computer (CompaqArmada E500) equipped with a standard interface card was used. Thecontrol algorithm was implemented in LabVIEW™, available from NationalInstruments™.

This embodiment is especially suitable for the use withradiopharmaceuticals typically used in PET and SPECT applications. Thedevice has been used to deliver radiopharmaceuticals with activityconcentrations as high as 1000 MBq/ml to patients, with an absoluteprecision of as good as 100 microliters and a relative precision ofbetter than 2% of the total activity delivered to the patient.

From the above description, it is clear that numerous variations of thedescribed device and method are possible, and the invention is in no waylimited to the above examples.

While the method has been described in a way that the volume of themetering section 8 of tubing is large enough to hold at the same timeall volumes of radiopharmaceutical to be injected together, the methodcan readily be adapted for use with a dose calibrator which measuresonly one of these volumes at a time. In this case, the activities A1,Ac′ and, optionally, Ac″ are measured directly and sequentially and neednot be calculated. Both variants of the method have in common that theactivity of a precisely known volume (in some arbitrary units) ismeasured, enabling determination of the activity concentration of theradiopharmaceutical.

The method can be extended to take into account the decrease of activityduring the dispensing procedure, in a straightforward manner bycalculating the decay during the (predetermined) time needed for thedispensing procedure.

The inventive device and method are not only useful for delivering aradiopharmaceutical to a human or animal body, but also in otherapplications, also of a non-medical nature, in which a precisely knownamount of activity is to be delivered to some destination. Accordingly,many variations of the types of tubing, valves, pumps etc, are possible.Specifically, other pump types than peristaltic pumps may be used. Infact, while the use of pumps is preferred, pumps may be omitted if thevial 2, the saline reservoir 5 or both are placed “top-down” in aposition higher than valves V1, V2 and the destination 16. Fluid flow isthen effected by gravity alone. Instead of pumps, flow meters shouldthen be provided, yielding volume information to the controller 13.

Different types of valves than the above-described two-way pinch valvesmay be used. Specifically, it may be advantageous to provide, as valveV1, a valve which can be switched to a third state such that liquid canflow between ports “a” and “c”. In this way, the sections of tubingbetween points A and B may be flushed with saline from reservoir 5,without the need of inserting a vial with saline instead of the vialwith the radiopharmaceutical during initialisation.

Any suitable activity detector may be used as a dose calibrator 9. Suchdetectors include standard Geiger-Müller counters, scintillatingcounters etc., which should be calibrated to yield a sufficientlyprecise measure of the actual activity in the metering section 8.

Additional safety measures may be taken, such as providing bubbledetectors in the fluid delivery path which stop operation immediately ifbubbles are detected. Bubble detectors are well known in the art.

LIST OF REFERENCE SIGNS

-   P1 first pump-   P2 second pump-   V1 first valve-   V2 second valve-   a, b, c connections of first valve-   d, e, f connection of second valve-   A inlet of radiopharmaceutical-   B, C, C′, C″ reference points-   D start of metering section-   E end of metering section-   M1, M2, M3 measurements-   A1, A2, Ar, Am, Ac′, Ac″ activities-   1 radiopharmaceutical-   2 vial-   3 shield-   4 tubing-   5 saline container-   6 tubing-   7 tubing-   8, 8′ metering section-   9 dose calibrator-   10 tubing-   11 injection needle-   12 waste-   13 controller-   21, 22, 23 volumes of radiopharmaceutical-   31 sliding element

The invention claimed is:
 1. A method of delivering a radioactiveliquid, the method comprising: performing an initialization phase,comprising: extracting at least a first amount of the radioactive liquidfrom a source of radioactive liquid; and measuring a radioactivity levelfor the first amount of the radioactive liquid; performing a calibrationphase, comprising: extracting a second amount of the radioactive liquidfrom the source of radioactive liquid; measuring a radioactivity levelfor the second amount of the radioactive liquid; and determining anactivity concentration of the radioactive liquid in the source ofradioactive liquid in system internal units based on the radioactivitylevel of the first amount of the radioactive liquid and theradioactivity level of the second amount of the radioactive liquid; andperforming a delivery phase, comprising: extracting a third amount ofthe radioactive liquid from the source of radioactive liquid to providea total dose of the radioactive liquid having a predeterminedradioactivity level, wherein the third amount is calculated based on atleast the activity concentration of the radioactive liquid in the sourceof radioactive liquid; and delivering the total dose of the radioactiveliquid.
 2. The method of claim 1, wherein the second amount of theradioactive liquid is between 20% and 80% of a sum of the first, second,and third amounts of the radioactive liquid.
 3. The method of claim 1,further comprising delivering the first and second amounts of theradioactive liquid after extracting the second amount of the radioactiveliquid.
 4. The method of claim 1, further comprising flushing a fluidline after delivering the total dose of the radioactive liquid.
 5. Themethod of claim 1, further comprising: transporting the first amount ofthe radioactive liquid to a metering section where the initializationphase is carried out; and transporting the second amount of theradioactive liquid to the metering section where the calibration phaseis carried out.
 6. The method of claim 1, further comprising measuring aradioactivity level of an amount of the radioactive liquid equal to thepredetermined radioactivity level.
 7. The method of claim 1, furthercomprising: transporting an amount of the radioactive liquid having aradioactivity level equal to the predetermined radioactivity level to ametering section; and measuring a radioactivity level of the amount ofthe radioactive liquid having a radioactivity level equal to thepredetermined radioactivity level in the metering section.
 8. The methodof claim 1, further comprising performing at least one more calibrationphase and delivery phase.
 9. A method of delivering a radioactiveliquid, the method comprising: performing a calibration phase,comprising: extracting a first amount of the radioactive liquid from asource of radioactive liquid; measuring a radioactivity level for thefirst amount of the radioactive liquid; determining an activityconcentration of the radioactive liquid in the source of radioactiveliquid in system internal units based on the radioactivity level of thefirst amount of the radioactive liquid; and performing a delivery phase,comprising: extracting a second amount of the radioactive liquid fromthe source of radioactive liquid to provide a total dose of theradioactive liquid having a predetermined radioactivity level, whereinthe second amount is calculated based on at least the activityconcentration of the radioactive liquid in the source of radioactiveliquid; and delivering the total dose of the radioactive liquid.
 10. Themethod of claim 9, wherein the first amount of the radioactive liquid isbetween 20% and 80% of a sum of the first and second amounts of theradioactive liquid.
 11. The method of claim 9, further comprisingflushing a fluid line after delivering the total dose of the radioactiveliquid.
 12. The method of claim 9, further comprising: transporting thefirst amount of the radioactive liquid to a metering section where thecalibration phase is carried out; and transporting the second amount ofthe radioactive liquid to the metering section.
 13. The method of claim9, further comprising measuring a radioactivity level of an amount ofthe radioactive liquid equal to the predetermined radioactivity level.14. The method of claim 9, further comprising: transporting an amount ofthe radioactive liquid having a radioactivity level equal to thepredetermined radioactivity level to a metering section; and measuring aradioactivity level of the amount of the radioactive liquid having aradioactivity level equal to the predetermined radioactivity level inthe metering section.
 15. The method of claim 9, further comprisingperforming at least one more calibration and delivery phases.
 16. Asystem for dispensing a radioactive liquid to a destination, the systemcomprising: a source of radioactive liquid; a fluid delivery pathdisposed between the source of radioactive liquid and the destination;an activity metering unit operable to determine a level of radioactivitywithin a metering section of the fluid delivery path; a valve adapted tobe placed in a first state for selectively connecting the source ofradioactive liquid to the fluid delivery path upstream of the activitymetering unit; and a control unit adapted to: place the valve in thefirst state to transport a first amount of the radioactive liquid fromthe source of radioactive liquid to the metering section; receive, fromthe activity metering unit, a measure of a level of radioactivity forthe first amount of the radioactive liquid; place the valve in the firststate to transport a second amount of the radioactive liquid from thesource of radioactive liquid to the metering section; receive, from theactivity metering unit, a measure of a level of radioactivity for thesecond amount of the radioactive liquid; determine an activityconcentration of the radioactive liquid in the source of radioactiveliquid in system internal units based on the level of radioactivity ofthe first amount and the level of radioactivity of the second amount;and place the valve in the first state to transport a third amount ofthe radioactive liquid from the source of radioactive liquid to providea total dose of radioactive liquid having a predetermined radioactivitylevel, wherein the third amount is calculated based on at least theactivity concentration of the radioactive liquid in the source ofradioactive liquid.
 17. The system of claim 16, wherein the valve isadapted for remote operation.
 18. The system of claim 16, wherein thevalve is further adapted to be placed in a second state for selectivelyconnecting a source of a flushing liquid to the fluid delivery pathupstream of the activity metering section.